Tmem175
Domain
Composed of two modules of six transmembranes, forming a homodimer with a tetrameric architecture. The six transmembrane regions of each module are tightly packed within each subunit without undergoing domain swapping. Forms a central ion-conduction pore lined by the side chains of the pore-lining helices. Conserved isoleucine residues (Ile-43 in the first module and Ile-268 in the second module) in the center of the pore serve as the gate in the closed conformation. In the widened channel in the open conformation, the same residues establish a constriction essential for potassium selectivity.
Function
Proton-activated proton channel that catalyzes proton efflux from endosomes and lysosomes to maintain a steady-state pH (PubMed:35750034). Activated at low pH (under pH 4.6) by luminal side protons: selectively mediates lysosomal proton release from lysosomes, eliciting a proton leak that balances V-ATPase activity to maintain pH homeostasis (By similarity). Regulation of lumenal pH stability is required for autophagosome-lysosome fusion (PubMed:26317472). Also acts as a potassium channel at higher pH, regulating potassium conductance in endosomes and lysosomes (PubMed:26317472, PubMed:33505021). Constitutes the pore-forming subunit of the lysoK(GF) complex, a complex activated by extracellular growth factors (PubMed:33505021). The lysoK(GF) complex is composed of TMEM175 and AKT (AKT1, AKT2 or AKT3), a major target of growth factor receptors: in the complex, TMEM175 channel is opened by conformational changes by AKT, leading to its activation (PubMed:33505021). The lysoK(GF) complex is required to protect neurons against stress-induced damage (PubMed:33505021).
Sequence Similarities
Belongs to the TMEM175 family.
Cellular localization
- Endosome membrane
- Multi-pass membrane protein
- Lysosome membrane
- Multi-pass membrane protein
Alternative names
Endosomal/lysosomal proton channel TMEM175, Potassium channel TMEM175, Transmembrane protein 175, mTMEM175